The outer limits of psychiatric genetics

The Wiring the Brain blog has a fantastic piece on the how whole genome sequencing is already showing us the limits of how we understand the genetics of mental illness.

Whole genome sequencing allows the entire length of someone’s DNA to be read and, when data from enough people has been collected, it’s possible to look for reliable links between genetic information and human traits.

The advantage of this technique is that it allows genetic links to be detected without needing a specific idea about what should link with what beforehand.

It’s often been cited as the ‘new hope’ for psychiatric genetics which attempts to understand the genetics of mental illness.

However, one difficulty with looking for genetic links with mental illness is that people diagnosed with conditions like schizophrenia or bipolar are unlikely to have exactly the same thing while the specific components are not perfectly measurable (there is no cut and dry way of classifying intrusive thoughts for example).

In addition, most genetic studies to date have found that changes in single genes can explain only a tiny fraction of the risk of developing a mental illness and are often present, although less frequently, in healthy people.

Owing to the fact that the heritability of mental illness can be quite high, the current thinking is that the risk is likely transmitted through lots of genes that, although individually have a small effect, can greatly increase the risk if transmitted together.

The Wiring the Brain post does a brilliant job of exploring why picking out these genes and genetic patterns may not just be a problem with not having enough data – but with the techniques themselves.

However, we will still likely be left with a situation where the statistical evidence we can get from considering the spectrum of mutations in single genes will run into mathematical limits. At some point it will be necessary to look for other types of evidence from outside the system. One type of evidence will come from analysing the biochemical pathways of the implicated genes – it is already becoming apparent that many such genes encode proteins that interact with each other…

The point about mathematical limits is an interesting one, as it may be that there are genes or genetic patterns which are important but have such a small effect that you would need a sample size so big (millions and millions of people perhaps) that your study would simply be impossible.

As the post indicates, this may kill the idea that the genetics of mental illness can be studied without any existing theories and just by looking at which links turn up.

It’s a bit like trying to work out how riots start by counting the different types of people in crowds and seeing which types of people are more likely to be present when a fight breaks out.

Without knowing about the roles of different people, you could easily conclude that the police are the ones responsible for the riot because they are always there in big numbers, while the firebrand orator demanding death to the government is irrelevant because there’s only one of him.

The Wiring the Brain piece covers this and several other issues and is one of the most interesting articles on psychiatric genetics I have read in a while. The blog, by the way, is consistently excellent, so definitely one to keep tabs on.

Link to Wiring the Brain on ‘Searching for a needle in a needle-stack’.

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